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Physiology & Behavior May 2018Cholecystokinin (CCK) and apolipoprotein A-IV (ApoA-IV) are gastrointestinal peptides that play an important role in controlling energy homeostasis. Lymphatic ApoA-IV...
Cholecystokinin (CCK) and apolipoprotein A-IV (ApoA-IV) are gastrointestinal peptides that play an important role in controlling energy homeostasis. Lymphatic ApoA-IV and plasma CCK secretion are mediated via a chylomicron formation-dependent pathway during a dietary lipid infusion. Given their similar roles as satiating proteins, the present study examines how the two peptides interact in their function. Specifically, this study sought to understand how ApoA-IV regulates CCK secretion. For this purpose, Cck gene expression in the small intestines of ApoA-IV knockout (ApoA-IV-KO) and wild-type (WT) mice were compared under an array of feeding conditions. When fed with a chow or high-fat diet (HFD), basal levels of Cck transcripts were significantly reduced in the duodenum of ApoA-IV-KO mice compared to WT mice. Furthermore, after an oral gavage of a lipid mixture, Cck gene expression in the duodenum was significantly reduced in ApoA-IV-KO mice relative to the change seen in WT mice. To determine the mechanism by which ApoA-IV modulates Cck gene expression, STC-1 cells were transfected with predesigned mouse lysophosphatidic acid receptor 5 (LPAR5) small interfering RNA (siRNA) to knockdown Lpar5 gene expression. In this in-vitro study, mouse recombinant ApoA-IV protein increased Cck gene expression in enteroendocrine STC-1 cells and stimulated CCK release from the STC-1 cells. However, the levels of CCK protein and Cck expression were attenuated when Lpar5 was knocked down in the STC-1 cells. Together these observations suggest that dietary lipid-induced ApoA-IV is associated with Cck synthesis in the duodenum and that ApoA-IV protein directly enhances CCK release through the activation of a LPAR5-dependent pathway.
Topics: Animals; Antioxidants; Apolipoproteins A; Cell Line, Transformed; Cholecystokinin; Dietary Fats; Dose-Response Relationship, Drug; Duodenum; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger; Receptors, Lysophosphatidic Acid; Time Factors; Triglycerides
PubMed: 29378187
DOI: 10.1016/j.physbeh.2018.01.019 -
Nature May 2024Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL)...
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a)). Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. ). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K7-8. We identify compounds that bind to apo(a) K7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).
Topics: Animals; Female; Humans; Male; Mice; Administration, Oral; Drug Discovery; Kringles; Lipoprotein(a); Macaca fascicularis; Mice, Transgenic; Small Molecule Libraries; Plasminogen; Species Specificity; Clinical Trials, Phase II as Topic; Apolipoproteins A
PubMed: 38720069
DOI: 10.1038/s41586-024-07387-z -
Current Opinion in Lipidology Aug 2022A 'proteoform' is defined as one specific protein structural form that results from the combination of allelic variation, alternative RNA splicing, and/or... (Review)
Review
PURPOSE OF REVIEW
A 'proteoform' is defined as one specific protein structural form that results from the combination of allelic variation, alternative RNA splicing, and/or posttranslational modifications (PTMs) in specific locations on the amino acid backbone. Apolipoproteins A1 and A2 are highly abundant apolipoproteins that mediate HDL structure and function. ApoA1 and apoA2 are known to undergo PTMs, which results in multiple proteoforms. However, the catalogue of apoA1 and apoA2 proteoforms as well as their associations with cardiometabolic health characteristics has not been described until recently. In this brief review, we discuss recent efforts to catalogue the spectrum of apoA1 and apoA2 proteoforms, to understand the relationships between the relative abundance of these proteoforms with cardiometabolic phenotypic characteristics, and we will discuss the implications of these findings to future research.
RECENT FINDINGS
A broad spectrum of apoA1 and apoA2 proteoforms has been characterized. Although, the types of apoA1 and A2 proteoforms are consistent across individuals, the relative abundances of proteoforms can vary substantially between individuals. Proteoform-specific associations with cardiometabolic characteristics in humans, independent of absolute apolipoprotein abundance, have been described. These recent findings suggest multiple levels of protein structural variation that arise from known and unknown metabolic pathways may be important markers or mediators of cardiometabolic health.
SUMMARY
Understanding the associations between apolipoprotein proteoforms and phenotype may lead to enhanced understanding of how apolipoproteins mediate lipid metabolism and affect atherosclerotic cardiovascular disease (ASCVD) risk, which may lead to discovery of novel markers of risk and/or key mechanistic insights that may drive further druggable targets for modifying lipid metabolism and reducing ASCVD risk.
Topics: Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins; Atherosclerosis; Humans; Protein Processing, Post-Translational
PubMed: 36082946
DOI: 10.1097/MOL.0000000000000840 -
Pediatric Research Aug 2023We assessed serum concentrations of pancreatic stone protein (PSP), copeptin, and apolipoprotein A-V (APOA5) biomarkers for the diagnosis and prognosis of pediatric...
BACKGROUND
We assessed serum concentrations of pancreatic stone protein (PSP), copeptin, and apolipoprotein A-V (APOA5) biomarkers for the diagnosis and prognosis of pediatric sepsis, a condition associated with high mortality.
METHODS
This prospective study included 180 children admitted to the Pediatric Intensive Care Unit and 100 healthy controls at Menoufia University Hospital. Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality-2 (PIM2), and Pediatric Sequential Organ Failure Assessment (pSOFA) scores were calculated. Serum PSP, copeptin and APOA5 were measured once within 24 h of admission.
RESULTS
PSP, copeptin, and APOA5 were significantly higher in the patients than in the controls (p < 0.001). PSP and copeptin were increased among children who required mechanical ventilation (MV), had multiple organ dysfunctions, and were non-survivors, but APOA5 was decreased in those children. Logistic regression analyses showed that high pSOFA, high PSP and copeptin, low APOA5, and use of MV were associated with mortality. The receiver operating characteristic revealed that the area under the curve (AUC) for APOA5, copeptin, and PSP (0.965, 0.960, and 0.868, respectively) demonstrated high sensitivity (96%, 94%, and 80%) for sepsis diagnosis. The AUC values for PSP, copeptin, and APOA5 were 0.709, 0.705, and 0.571, respectively, with sensitivities of 74%, 58%, and 58% for mortality prediction.
CONCLUSIONS
PSP, copeptin, and APOA5 are promising diagnostic biomarkers for pediatric sepsis but inadequate predictors of mortality.
IMPACT
Apolipoprotein A-V (APOA5), copeptin, and pancreatic stone protein (PSP) are acute-phase proteins with diagnostic value in evaluating critically ill pediatric patients with sepsis and detecting sepsis severity. PSP and copeptin had the power to discriminate non-survivors from survivors. APOA5 was less powerful than the other biomarkers in discriminating between survivors and non-survivors.
Topics: Humans; Child; Apolipoprotein A-V; Prospective Studies; Lithostathine; Prognosis; Biomarkers; Sepsis; ROC Curve
PubMed: 36755189
DOI: 10.1038/s41390-023-02499-0 -
JCI Insight Oct 2023Oxidized apolipoprotein B (oxLDL) and oxidized ApoA-I (oxHDL) are proatherogenic. Their prognostic value for assessing high-risk plaques by coronary computed tomography... (Observational Study)
Observational Study
BACKGROUND
Oxidized apolipoprotein B (oxLDL) and oxidized ApoA-I (oxHDL) are proatherogenic. Their prognostic value for assessing high-risk plaques by coronary computed tomography angiography (CCTA) is missing.
METHODS
In a prospective, observational study, 306 participants with cardiovascular disease (CVD) had extensive lipoprotein profiling. Proteomics analysis was performed on isolated oxHDL, and atherosclerotic plaque assessment was accomplished by quantitative CCTA.
RESULTS
Patients were predominantly White, overweight men (58.5%) on statin therapy (43.5%). Increase in LDL-C, ApoB, small dense LDL-C (P < 0.001 for all), triglycerides (P = 0.03), and lower HDL function were observed in the high oxLDL group. High oxLDL associated with necrotic burden (NB; β = 0.20; P < 0.0001) and fibrofatty burden (FFB; β = 0.15; P = 0.001) after multivariate adjustment. Low oxHDL had a significant reverse association with these plaque characteristics. Plasma oxHDL levels better predicted NB and FFB after adjustment (OR, 2.22; 95% CI, 1.27-3.88, and OR, 2.80; 95% CI, 1.71-4.58) compared with oxLDL and HDL-C. Interestingly, oxHDL associated with fibrous burden (FB) change over 3.3 years (β = 0.535; P = 0.033) when compared with oxLDL. Combined Met136 mono-oxidation and Trp132 dioxidation of HDL showed evident association with coronary artery calcium score (r = 0.786; P < 0.001) and FB (r = 0.539; P = 0.012) in high oxHDL, whereas Met136 mono-oxidation significantly associated with vulnerable plaque in low oxHDL.
CONCLUSION
Our findings suggest that the investigated oxidized lipids are associated with high-risk coronary plaque features and progression over time in patients with CVD.
CLINICALTRIALS
gov NCT01621594.
FUNDING
National Heart, Lung, and Blood Institute at the NIH Intramural Research Program.
Topics: Humans; Male; Apolipoprotein A-I; Apolipoproteins B; Cardiovascular Diseases; Cholesterol, LDL; Plaque, Atherosclerotic; Prospective Studies
PubMed: 37698922
DOI: 10.1172/jci.insight.172893 -
Hepatology International Jun 2023Since hepatocytes produce majority of serum proteins, patients with cirrhosis display substantial alterations in the serum proteome. The aim of the current study was to...
BACKGROUND AND AIM
Since hepatocytes produce majority of serum proteins, patients with cirrhosis display substantial alterations in the serum proteome. The aim of the current study was to characterize these changes and to study the prognostic utility of hepatocellular proteins available in routine clinical testing.
METHODS
Sera from 29 healthy controls and 43 patients with cirrhosis were subjected to untargeted proteomic analysis. Unsupervised hierarchical clustering was performed with Perseus software and R. Ingenuity pathway analysis (IPA) suggested upstream regulators that were validated in liver tissues. The behavior and prognostic usefulness of selected biomarkers was investigated in 61 controls and 285 subjects with decompensated cirrhosis.
RESULTS
Proteomics uncovered 65 and 16 hepatocellular serum proteins that are significantly downregulated or upregulated in patients with cirrhosis vs. controls. Hierarchical clustering revealed two main clusters and six sub-clusters. IPA identified HNF4α and IL-6 as the two major upstream regulators that were confirmed by hepatic gene expression analyses. Among pseudocholinesterase, transferrin, transthyretin, albumin, and apolipoprotein AI (Apo-AI), Apo-AI was the best predictor of 90-days transplant-free survival (AUROC 0.678; p = 0.0001) and remained an independent predictor in multivariable Cox independently of the presence of acute-on-chronic liver failure.
CONCLUSION
Our study reveals cirrhosis-associated changes in hepatocellular serum proteins and underlying transcription factors. Serum apolipoprotein AI may constitute a useful prognostic adjunct in patients with decompensated cirrhosis.
Topics: Humans; Carcinoma, Hepatocellular; Apolipoprotein A-I; Proteomics; Liver Neoplasms; Biomarkers; Liver Cirrhosis; Prognosis; Fibrosis; Blood Proteins
PubMed: 36652164
DOI: 10.1007/s12072-022-10473-x -
Journal of Clinical Lipidology 2022Apolipoproteins are associated with risk of coronary heart disease but the association with risk of incident atrial fibrillation (AF) has been inconsistent.
BACKGROUND
Apolipoproteins are associated with risk of coronary heart disease but the association with risk of incident atrial fibrillation (AF) has been inconsistent.
OBJECTIVES
This study investigated the association of apolipoproteins A-1 (apoA-1) and B (apoB), and lipid levels including triglyceride (TG), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), with the risk of new-onset AF.
METHODS
A total of 2533 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 years, were studied. Cox proportional hazards adjusted for potential confounders was used to estimate hazard ratio (HR) of incident events across serum lipid, lipoprotein, and apoA-1 and apoB concentrations.
RESULTS
During the mean follow-up of 22.4 years, 594 AF cases occurred. Cox proportional hazards regression indicated that higher serum HDL-C and apoA-1 concentrations were associated with lower risk of AF [the extreme-quartile multivariable-adjusted HR 0.72 (95% CI 0.57-0.92, P = 0.02) for HDL-C, and 0.72 (95% CI 0.52-1.00, P = 0.05)] for apoA-1]. No significant associations were observed for apoB and other lipids (TC, VLDL-C, LDL-C, non-HDL-C, and TG) with risk of incident AF.
CONCLUSION
Over the time of follow-up in this study lower new-onset incident AF was in association with higher HDL-C and apo-A1 levels. Future studies should investigate mechanisms underlying the association of low HDL-C and low apoA1 with higher risk of incident AF.
Topics: Apolipoprotein A-I; Apolipoproteins; Apolipoproteins B; Atrial Fibrillation; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Heart Disease Risk Factors; Humans; Male; Prospective Studies; Risk Factors; Triglycerides
PubMed: 35525793
DOI: 10.1016/j.jacl.2022.04.003 -
Clinica Chimica Acta; International... Dec 2020Lipoprotein(a) (Lp(a)) is an independent risk factor in the development of atherosclerotic cardiovascular diseases (ASCVD) and calcific aortic valve disease (CAVD)....
Lipoprotein(a) (Lp(a)) is an independent risk factor in the development of atherosclerotic cardiovascular diseases (ASCVD) and calcific aortic valve disease (CAVD). Lp(a) is an LDL-like particle to which apolipoprotein (a) (apo(a)) is covalently bound. Apo(a) contains a variable number of kringle IV repeats, a kringle V and a protease domain. Serum/plasma Lp(a) concentrations are traditionally expressed as total particle mass in mg/L. Concern has arisen lately as flawed Lp(a) mass tests have masked its clinical utility. The determinants of variability in Lp(a) composition were investigated, including the apo(a) size polymorphism, post-translational modifications -N- and O-glycosylation- and the lipid:protein ratio. Depending on the number of kringle IV-2 repeats, the theoretical protein content of the Lp(a) particle varies between 30 and 46 (w/w) %, which inescapably confounds Lp(a) mass measurements. The authors advocate that reporting of Lp(a) particle concentrations in mass units is metrologically inappropriate and should be abandoned, as it results in systematically biased Lp(a) results. Enabling technology, such as mass spectrometry, allows unequivocal molecular characterization of the apo(a) measurand(s) and accurate quantitation of apo(a) in molar units, unaffected by apo(a) size polymorphism. To guarantee that Lp(a)/apo(a) tests are fit-for-clinical-purpose, basic metrology principles should be implemented upfront during test development.
Topics: Apolipoproteins A; Apoprotein(a); Humans; Kringles; Lipoprotein(a); Precision Medicine
PubMed: 33058841
DOI: 10.1016/j.cca.2020.10.010 -
Lipids in Health and Disease Sep 2023Lipoprotein (a) [Lp(a)] is an apoB100-containing lipoprotein with high levels being positively associated with atherosclerotic cardiovascular disease. Lp(a) levels are...
BACKGROUND
Lipoprotein (a) [Lp(a)] is an apoB100-containing lipoprotein with high levels being positively associated with atherosclerotic cardiovascular disease. Lp(a) levels are genetically determined. However, previous studies report a negative association between Lp(a) and saturated fatty acid intake. Currently, apoB100 lowering therapies are used to lower Lp(a) levels, and apheresis therapy is FDA approved for patients with extreme elevations of Lp(a). The current study analyzed the association of free-living diet components with plasma Lp(a) levels.
METHODS
Dietary composition data was collected during screening visits for enrollment in previously completed lipid and lipoprotein metabolism studies at Columbia University Irving Medical Center via a standardized protocol by registered dietitians using 24 hour recalls. Data were analyzed with the Nutrition Data System for Research (Version 2018). Diet quality was calculated using the Healthy Eating Index (HEI) score. Fasting plasma Lp(a) levels were measured via an isoform-independent ELISA and apo(a) isoforms were measured using gel electrophoresis.
RESULTS
We enrolled 28 subjects [Black (n = 18); Hispanic (n = 7); White (n = 3)]. The mean age was 48.3 ± 12.5 years with 17 males. Median level of Lp(a) was 79.9 nmol/L (34.4-146.0) and it was negatively associated with absolute (grams/day) and relative (percent of total calories) intake of dietary saturated fatty acids (SFA) (R = -0.43, P = 0.02, SFA …(% CAL): R = -0.38, P = 0.04), palmitic acid intake (R = -0.38, P = 0.05), and stearic acid intake (R = -0.40, P = 0.03). Analyses of associations with HEI score when stratified based on Lp(a) levels > or ≤ 100 nmol/L revealed no significant associations with any of the constituent factors.
CONCLUSIONS
Using 24 hour recall, we confirm previous findings that Lp(a) levels are negatively associated with dietary saturated fatty acid intake. Additionally, Lp(a) levels are not related to diet quality, as assessed by the HEI score. The mechanisms underlying the relationship of SFA with Lp(a) require further investigation.
Topics: Male; Humans; Adult; Middle Aged; Diet; Lipoprotein(a); Apolipoproteins A; Fasting; Energy Intake
PubMed: 37670291
DOI: 10.1186/s12944-023-01884-2 -
Current Atherosclerosis Reports Jul 2022The elevated adverse cardiovascular event rate among patients with low high-density lipoprotein cholesterol (HDL-C) formed the basis for the hypothesis that elevating... (Review)
Review
PURPOSE OF REVIEW
The elevated adverse cardiovascular event rate among patients with low high-density lipoprotein cholesterol (HDL-C) formed the basis for the hypothesis that elevating HDL-C would reduce those events. Attempts to raise endogenous HDL-C levels, however, have consistently failed to show improvements in cardiovascular outcomes. However, steady-state HDL-C concentration does not reflect the function of this complex family of particles. Indeed, HDL functions correlate only weakly with serum HDL-C concentration. Thus, the field has pivoted from simply raising the quantity of HDL-C to a focus on improving the putative anti-atherosclerotic functions of HDL particles. Such functions include the ability of HDL to promote the efflux of cholesterol from cholesterol-laden macrophages. Apolipoprotein A-I (apoA-I), the signature apoprotein of HDL, may facilitate the removal of cholesterol from atherosclerotic plaque, reduce the lesional lipid content and might thus stabilize vulnerable plaques, thereby reducing the risk of cardiac events. Infusion of preparations of apoA-I may improve cholesterol efflux capacity (CEC). This review summarizes the development of apoA-I therapies, compares their structural and functional properties and discusses the findings of previous studies including their limitations, and how CSL112, currently being tested in a phase III trial, may overcome these challenges.
RECENT FINDINGS
Three major ApoA-I-based approaches (MDCO-216, CER-001, and CSL111/CSL112) have aimed to enhance reverse cholesterol transport. These three therapies differ considerably in both lipid and protein composition. MDCO-216 contains recombinant ApoA-I Milano, CER-001 contains recombinant wild-type human ApoA-I, and CSL111/CSL112 contains native ApoA-I isolated from human plasma. Two of the three agents studied to date (apoA-1 Milano and CER-001) have undergone evaluation by intravascular ultrasound imaging, a technique that gauges lesion volume well but does not assess other important variables that may relate to clinical outcomes. ApoA-1 Milano and CER-001 reduce lecithin-cholesterol acyltransferase (LCAT) activity, potentially impairing the function of HDL in reverse cholesterol transport. Furthermore, apoA-I Milano can compete with and alter the function of the recipient's endogenous apoA-I. In contrast to these agents, CSL112, a particle formulated using human plasma apoA-I and phosphatidylcholine, increases LCAT activity and does not lead to the malfunction of endogenous apoA-I. CSL112 robustly increases cholesterol efflux, promotes reverse cholesterol transport, and now is being tested in a phase III clinical trial. Phase II-b studies of MDCO-216 and CER-001 failed to produce a significant reduction in coronary plaque volume as assessed by IVUS. However, the investigation to determine whether the direct infusion of a reconstituted apoA-I reduces post-myocardial infarction coronary events is being tested using CSL112, which is dosed at a higher level than MDCO-216 and CER-001 and has more favorable pharmacodynamics.
Topics: Acute Coronary Syndrome; Apolipoprotein A-I; Atherosclerosis; Cholesterol; Cholesterol, HDL; Humans
PubMed: 35524914
DOI: 10.1007/s11883-022-01025-7